rs746643773

Positions:

• chr2-29228940-C-A
• chr2-29228940-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_004304.5(ALK):​c.2759G>T​(p.Gly920Val) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G920D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000030 (0 hom., cov: 23)
  • Exomes 𝑓: 0.00024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.35

Genes affected

ALK (HGNC:427): (ALK receptor tyrosine kinase) This gene encodes a receptor tyrosine kinase, which belongs to the insulin receptor superfamily. This protein comprises an extracellular domain, an hydrophobic stretch corresponding to a single pass transmembrane region, and an intracellular kinase domain. It plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. This gene has been found to be rearranged, mutated, or amplified in a series of tumours including anaplastic large cell lymphomas, neuroblastoma, and non-small cell lung cancer. The chromosomal rearrangements are the most common genetic alterations in this gene, which result in creation of multiple fusion genes in tumourigenesis, including ALK (chromosome 2)/EML4 (chromosome 2), ALK/RANBP2 (chromosome 2), ALK/ATIC (chromosome 2), ALK/TFG (chromosome 3), ALK/NPM1 (chromosome 5), ALK/SQSTM1 (chromosome 5), ALK/KIF5B (chromosome 10), ALK/CLTC (chromosome 17), ALK/TPM4 (chromosome 19), and ALK/MSN (chromosome X).[provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5	c.2759G>T	p.Gly920Val	missense_variant	16/29	ENST00000389048.8
ALK	XR_001738688.3	n.3668+18G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.2759G>T	p.Gly920Val	missense_variant	16/29	1	NM_004304.5	P1
ALK	ENST00000618119.4	c.1628G>T	p.Gly543Val	missense_variant	15/28	5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 3 AN: 98516 Hom.: 0 Cov.: 23 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000116

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000187

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000781

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000236 AC: 175 AN: 741622 Hom.: 0 Cov.: 22 AF XY: 0.000253 AC XY: 95 AN XY: 375390

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.000496

Gnomad4 ASJ exome AF: 0.000130

Gnomad4 EAS exome AF: 0.000493

Gnomad4 SAS exome AF: 0.000708

Gnomad4 FIN exome AF: 0.000253

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.000227

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000304 AC: 3 AN: 98534 Hom.: 0 Cov.: 23 AF XY: 0.0000418 AC XY: 2 AN XY: 47882

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000116

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000187

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000774

Alfa AF: 0.000506 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.7	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.3	D;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0050	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.58		Loss of disorder (P = 0.0177);.;
MVP		0.73
MPC		0.79
ClinPred		0.87	D
GERP RS		5.2
Varity_R		0.79
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs746643773; hg19: chr2-29451806;